(ELCC 2021 Virtual) Mar 25, 2021 - Clinical activity with a second drug inhibiting KRASG12C confirms its role as a therapeutic target in patients with advanced non-small-cell lung cancer (NSCLC) harbouring this mutation, according to results from a study with the KRASG12C inhibitor adagrasib reported at the European Lung Cancer Virtual Congress 2021. “As we strive to identify the oncogenic driver in more and more of our patients with NSCLC, it becomes critical that we develop therapies that can target these identified oncogenic drivers,” said lead author Gregory Riely, from Memorial Sloan Kettering Cancer Center, New York, USA.

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H. Jack West, MD (Posted: March 25, 2021)

Important work, especially data on co-mutations with KRAS G12C. There's a great deal more to learn in coming years. For now, these data with adagrasib look slightly superior to what we've seen with sotorasib, but we await far more data on combinations and in different settings in NSCLC in the coming years. I'm very hopeful that KRAS G12C is poised to become a large molecular subset for whom we'll have a greater understanding and steadily improving treatment options in the coming years.

(Roche) Mar 22, 2021 - Roche today announced that the Phase III IMpower010 study evaluating Tecentriq® (atezolizumab), compared with best supportive care (BSC), met its primary endpoint of disease-free survival (DFS) at the interim analysis. Tecentriq showed a statistically significant improvement in DFS as adjuvant therapy following surgery and chemotherapy in all randomised Stage II-IIIA populations with non-small cell lung cancer (NSCLC). The magnitude of DFS benefit was particularly pronounced in the PD-L1-positive population.

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H. Jack West, MD (Posted: March 22, 2021)

This is the first of likely several trials of adjuvant/neoadjuvant immunotherapy that will prove to be positive based on a surrogate endpoint, but here we have learned that it's especially favorable in those with PD-L1 positive cancers (which is the positive spin on "it was decidedly unimpressive in patients with PD-L1 negative cancers"), and with it reaching statistical significance for DFS on an interim analysis and no reported OS results, I suspect that we'll be left debating 1) whether statistical significance should imply clinical significance, 2) whether a DFS benefit that I'm going to predict is far less impressive than the HR of 0.17 seen for DFS on ADAURA should lead to a change in practice without seeing an improvement in OS, and 3) whether we should exclude patients who have PD-L1 <1% who (for the sake of argument I'll predict) show no meaningful improvement in DFS, let alone OS, with adjuvant atezolizumab. On top of this, we'll have room to debate whether FDA's shift to a mindset of providing the most liberal path to approval that can possibly be justified, not really filtering for clinically significant benefit, and then abrogating any responsibility for difficult judgment on appropriate use in practice to rank and file clinicians who won't have time or ability to focus on careful assessment of the data beyond being detailed by pharma reps. Also, we'll need to factor in not only the very significant financial cost of prolonged immunotherapy but the real risk of chronic, even permanent, treatment-induced toxicities from immunotherapy in patients who have a significant chance of already being cured from the treatments they'd have already received. I suspect that the results of this trial will compare unfavorably to the magnitude of benefit in terms of DFS that we saw with adjuvant osimertinib in the ADAURA trial, and this will lead to refinement of our question of how much we should focus on DFS and other surrogate endpoints like pathologic complete response rates as sufficient to change our practice, especially when "statistical significance" does not necessarily imply clinical significance.

(Pfizer) Mar 3, 2021 - The U.S. Food and Drug Administration (FDA) approved Pfizer Inc.’s supplemental New Drug Application (sNDA) for LORBRENA® (lorlatinib), expanding the indication to include first-line treatment of people with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). LORBRENA is now indicated for adults with metastatic NSCLC whose tumors are ALK-positive as detected by an FDA-approved test. The FDA action also converts the 2018 accelerated approval to full approval. The application was approved under the FDA’s Real-Time Oncology Review (RTOR) pilot program.

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H. Jack West, MD (Posted: March 05, 2021)

Lorlatinib is an excellent ALK inhibitor, but beating crizotinib as first line therapy for patients with ALK-positive advanced NSCLC only puts it on par with alectinib as a current standard of care or other 2nd generation ALK inhibitors also superior to crizotinib and approved in this setting. Lorlatinib has good activity, both extracranial and intracranial, but its toxicity profile is somewhat idiosyncratic, particularly the neuro-behavioral issues. I do not think it emerges as offering a clear incremental benefit over alectinib. Moreover, using lorlatinib first line means that it isn't available as second line therapy, where it is arguably the leading option after progression on alectinib or another ALK inhibitor.